Cognitive control and executive function are similar terms used to describe our ability to direct thought and action based on our goals and intentions, rather than being driven automatically by the world around us. Current theories of cognitive control propose that the prefrontal cortex (PFC) is a brain region that is critical for tis ability. The PFC has extensive, reciprocal projections to both cortical and subcortical regions and therefore is in a privileged position to be a source of top-down signals that could sculpt behavior. Building on the progress we have made in the previous funding period, the overall aim of the current proposal is to further advance and refine our understanding of the functional organization of PFC and the neural mechanisms by which the PFC can provide top-down signals that modulate incoming sensory information. We propose that the PFC stores the highest level of representations such as rules and goals, and it is the active maintenance of these representations that bias information processing elsewhere in the brain influencing how we ultimately make decisions and act. In humans, frontal lobe function has been extensively researched both through the careful study of neurological patients with focal lesions (usually due to stroke and traumatic brain injury) and using functional MRI (fMRI) with healthy young subjects. However, there has been surprisingly little work combining these two approaches. Lesion and fMRI methodologies can complement each other in significant ways, and so when combined can be a powerful approach for studying brain-behavior relationships. In this proposal, such a convergent approach will be implemented. Basic knowledge about PFC function and cognitive control can provide substantial insights into the nature of a large number of psychiatric and neurological disorders affecting PFC function such as schizophrenia, dementia, stroke and traumatic brain injury; as well as many other conditions such as attention-deficit disorder, substance addiction and normal aging, that are proposed to involve selective dysfunction of frontal brain systems. Moreover, cognitive and behavioral deficits from PFC damage are particularly challenging to treat. A greater understanding of frontal lobe function is necessary for developing effective therapeutic interventions. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will advance our understanding of the role of the frontal lobes in goal-directed behavior. Many psychiatric and neurological disorders such as schizophrenia dementia, stroke and traumatic brain injury affect frontal lobe function; and many other conditions such as attention-deficit disorder, substance addiction and normal aging, are proposed to involve selective dysfunction of frontal brain systems. The proposed research is also relevant to NIH's mission because it will lead to basic knowledge about frontal lobe function that can provide valuable insights into the understanding, diagnosis and treatment of a wide range of clinical conditions.